Single-nucleotide polymorphisms (SNPs) in DNA duplexes in human genomics play a key role in several hundreds of diseases. One of the central challenges is the detection and identification of these SNPs and miniaturized assays such as microarrays play an important role to allow for a massively parallelized readout in combination with limited sample volumes [Ng et al., Analytical and Bioanalytical Chemistry 386, p 427 (2006)]. Disadvantages are the long reaction times at the scale of at least 16 hours, the complete lack of dynamic information on the DNA binding kinetics, the need for fluorescent labelling of the target DNA, and the sophisticated optical readout techniques. Also, microarrays are in principle limited to the detection of known mutations albeit there is recent progress to exploit the thermodynamic aspects of probe DNA-target DNA recognition to identify SNPs even in the presence of wild-type DNA [Hooyberghs et al., Physical Review E 81, 012901 (2010)].
Alternatively, mutation analysis can be performed using techniques that exploit the denaturation of double-stranded (ds) DNA rather than the hybridization process. The best known examples are real-time PCR (polymerase chain reaction) with associated melting-curve analysis [Tindall et al., Human Mutation 30, p 876 (2009)] and denaturing gradient gel electrophoresis DGGE [Lodewyckx et al., Human Mutation 18, p 243 (2001)]. Both techniques rely on the fact that DNA duplexes containing a SNP are less stable than complementary duplexes. This leads to lower denaturation (melting) temperatures for SNP-type DNA duplexes as compared to the complementary duplexes. Nevertheless, both techniques require expensive instrumentation, real-time PCR relies on the use of fluorescent labels, and DGGE is not suitable for high-throughput analysis.
Due to the inherent complexity of microarrays and the established denaturation-based approaches, strong efforts are put into the development of label-free detection techniques based on electronic readout principles. One of these electronic routes is the direct sequencing of DNA fragments with solid-state- and haemolysin nanopores, utilizing the current-blocking effect [Clarke et al., Nature Nanotechnology 4, 265-270 (2010)]. Alternatively, the DNA switching method on gold electrodes proposed by Rant [Rant et al., Proceedings of the National Academy of Sciences of the United States of America 104, p 17364 (2007] allows for real-time monitoring of hybridization and denaturation with the possibility to distinguish between complementary and mismatched fragments. Despite the method requires no fluorescent labelling of the target DNA, labels are involved on the probe DNA.
A method without any labelling and auxiliary chemistry is the solution-gate field-effect transistor (FET) device with the probe DNA directly immobilized on the gate oxide [Ingebrandt et al Biosensors and Bioelectronics 22, p 2834 (2007)]. Real-time monitoring of hybridization is in principle possible and the FETs can discriminate between complementary and mismatched strands under ex situ conditions. The sensing effect of FETs is attributed to the intrinsic negative charge of ss- and ds-DNA fragments and to a redistribution of ionic charges at the proximity of the gate insulator during hybridization [Poghossian et al., Sensors and Actuators B—Chemical 111, p 470 (2005)].
DNA-hybridization sensors based on impedance spectroscopy have been established with screen-printed carbon electrodes [Davis et al., Analytical Chemistry 79, 1153-1157 (2007)], mixed self-assembled monolayers on gold electrodes using a redox system, conjugated polymers, and GaN nanowires [Park et al., Sensors 9, 9513-9532 (2009)].
Despite of all recent progress, the aforementioned electronic- or opto-electronic methods for DNA sensing have in common that there are at least two or more of the following drawbacks:                need for high-end instrumentation and incompatibility with upgrading towards high-throughput assays;        need for additional chemicals such as fluorescent dyes or redox mediators;        lack of sensor-regeneration capacity;        missing proof that the sensor response is intrinsic and unaffected by conductivity effects related to temperature or ionic composition of the buffer liquids;        insufficient statistics to demonstrate the reproducibility;        lack of dynamic information on the kinetics of hybridization- or denaturation events.        
As a conclusion, the state of the art techniques used in genetic research laboratories do not meet the criteria of being label-free, fast and cheap. Furthermore, these techniques allow only for single-term measurements and cannot be used repetitively. There is hence still a need to further elaborate the detection and identification of single-nucleotide polymorphisms (SNPs).